Anti-B7-H1 antibodies for treating tumors

ABSTRACT

Provided herein are methods of treating B7-H1-expressing tumors comprising administering an effective amount of MEDI4736 or an antigen-binding fragment thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage application of InternationalApplication No. PCT/EP2014/069425, filed on Sep. 11, 2014, saidInternational Application No. PCT/EP2014/069425 claims benefit under 35U.S.C. § 119(e) of U.S. Provisional Application No. 61/876,509, filedSep. 11, 2013, U.S. Provisional Application No. 61/971,212, filed Mar.27, 2014, U.S. Provisional Application No. 61/978,401, filed Apr. 11,2014 and U.S. Provisional Application No. 62/003,349, filed May 27,2014. Each of the above listed applications is incorporated by referenceherein in its entirety for all purposes.

REFERENCE TO THE SEQUENCE LISTING

This application incorporates by reference a Sequence Listing submittedwith this application as text file entitled B7H1-200US1_SL, created onMar. 7, 2016, and having a size of 13.4 megabytes.

BACKGROUND

Cancer continues to be a major global health burden. Despite progress inthe treatment of cancer, there continues to be an unmet medical need formore effective and less toxic therapies, especially for those patientswith advanced disease or cancers that are resistant to existingtherapeutics.

The immune system is capable of identifying tumor-associated antigensand eliminating the cancerous cells expressing them. This process oftumor immune surveillance, or tumor immunoediting, plays an importantrole in preventing and combating the growth of tumors, and levels oftumor-infiltrating lymphocytes, and more specifically cytotoxic T cells,have been correlated to improved prognosis in a number of cancers. Thus,enhancing the immune response may provide a means to control tumors.

B7-H1 (also known as programmed death ligand 1 (PD-L1) or CD274) is partof a complex system of receptors and ligands that are involved incontrolling T-cell activation. In normal tissue, B7-H1 is expressed on Tcells, B cells, dendritic cells, macrophages, mesenchymal stem cells,bone marrow-derived mast cells, as well as various nonhematopoieticcells. Its normal function is to regulate the balance between T-cellactivation and tolerance through interaction with its two receptors:programmed death 1 (also known as PD-1 or CD279) and CD80 (also known asB7-1).

B7-H1 is also expressed by tumors and acts at multiple sites to helptumors evade detection and elimination by the host immune system. B7-H1is expressed in a broad range of cancers with a high frequency. In somecancers, expression of B7-H1 has been associated with reduced survivaland unfavorable prognosis. Antibodies that block the interaction betweenB7-H1 and its receptors are able to relieve B7-H1-dependentimmunosuppressive effects and enhance the cytotoxic activity ofantitumor T cells in vitro.

MEDI4736 is a human monoclonal antibody directed against human B7-H1that is capable of blocking the binding of B7-H1 to both the PD-1 andCD80 receptors. Thus, given the high unmet need of treating tumors,including those with a high incidence rate as well as less common typeswith limited treatment options and poor outcomes, the effect of MEDI4736on tumors in human patients was examined.

BRIEF SUMMARY

Methods of administering MEDI4736 to human patients and methods oftreating tumors in human patients using MEDI4736 are provided herein.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering MEDI4736 or an antigen-bindingfragment thereof to the patient, wherein the administration decreasestumor size.

In certain aspects, a method of minimizing anti-drug antibodies producedby a human patient with a B7-H1-expressing tumor, wherein the patient isbeing treated with an anti-B7-H1 antibody or antigen-binding fragmentthereof, comprises administering MEDI4736 or an antigen-binding fragmentthereof to the patient.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering MEDI4736 or an antigen-bindingfragment thereof to the patient, wherein the administration produces anAUC (tau) of about 100 to about 2,500 d·μg/mL.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering MEDI4736 or an antigen-bindingfragment thereof to the patient, wherein the administration produces aCmax of about 15 to about 350 μg/mL.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering MEDI4736 or an antigen-bindingfragment thereof to the patient, wherein the half-life of the MEDI4736or the antigen-binding fragment thereof is about 5 to about 25 days.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering MEDI4736 or an antigen-bindingfragment thereof to the patient, wherein the clearance of the MEDI4736or the antigen-binding fragment thereof is about 1-10 ml/day/kg.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering to the patient a dose of about 3mg/kg MEDI4736 or an antigen-binding fragment thereof.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering to the patient a dose of about 15mg/kg MEDI4736 or an antigen-binding fragment thereof.

In certain aspects, a method of treating a B7-H1-expressing tumor in ahuman patient comprises administering MEDI4736 or an antigen-bindingfragment thereof, wherein administration of 1 mg/kg of the MEDI4736 oran antigen-binding fragment thereof is sufficient to reduce tumor size.

In some embodiments, at least two doses of the MEDI4736 or theantigen-binding fragment thereof are administered. In some embodiments,at least 3 doses of the MEDI4736 or the antigen-binding fragment thereofare administered. In some embodiments, at least 5 doses of the MEDI4736or the antigen-binding fragment thereof are administered.

In some embodiments, the administration reduces tumor growth. In someembodiments, the administration decreases tumor size. In someembodiments, the administration decrease tumor size by at least 25%. Insome embodiments, the administration decrease tumor size by at least50%. In some embodiments, the administration decrease tumor size by atleast 75%.

In some embodiments, the administration minimizes the likelihood ofanti-drug antibodies produced by the patient. In some embodiments, nomore than 10% of patients treated with MEDI4736 produce anti-drugantibodies. In some embodiments, no more than 9% of patients treatedwith MEDI4736 produce anti-drug antibodies. In some embodiments, no morethan 8% of patients treated with MEDI4736 produce anti-drug antibodies.In some embodiments, no more than 7% of patients treated with MEDI4736produce anti-drug antibodies.

In some embodiments, the administration produces a median range of AUC(tau) measurements. Thus, for example, in some embodiments, theadministration produces an AUC (tau) of about 100 to about 2,500d·μg/mL. In some embodiments, the administration produces a median rangeof Cmax measurements. Thus, for example, in some embodiments, theadministration produces a Cmax of about 15 to about 350 μg/mL. In someembodiments, the administration produces a median range of half-lifemeasurements. Thus, for example, in some embodiments, the half-life ofthe MEDI4736 or the antigen-binding fragment thereof is about 5 to about25 days. In some embodiments, the administration produces a median rangeof clearance measurements. Thus, for example, in some embodiments, theclearance of the MEDI4736 or the antigen-binding fragment thereof isabout 1-10 ml/day/kg.

In some embodiments, about 0.1, about 0.3, about 1, about 3, about 10,or about 15 mg/kg MEDI4736 or an antigen-binding fragment thereof isadministered. In some embodiments, about 1 mg/kg MEDI4736 or anantigen-binding fragment thereof is administered. In some embodimentsabout 3 mg/kg MEDI4736 or an antigen-binding fragment thereof isadministered. In some embodiments, about 10 mg/kg MEDI4736 or anantigen-binding fragment thereof is administered. In some embodiments,about 15 mg/kg MEDI4736 or an antigen-binding fragment thereof isadministered.

In some embodiments, the administration is repeated about every 14 to 21days. In some embodiments, the administration is repeated about every 14days. In some embodiments, the administration is repeated about every 21days.

In some embodiments, the tumor size decreases or tumor growth isreduced, and MEDI4736 or an antigen-binding fragment thereof issubsequently administered as a maintenance therapy about every 2 months.

In some embodiments, the tumor size decreases by at least 25% withinabout 6 weeks. In some embodiments, the administration decrease tumorsize by at least 50%. In some embodiments, the tumor size decreases byat least 50% within about 10 weeks. In some embodiments, theadministration decrease tumor size by at least 75%. In some embodiments,the tumor size decreases by at least 75% within about 10 weeks.

In some embodiments, the administration results in a partial response.In some embodiments, the administration results in a complete response.In some embodiments, the administration increases progression freesurvival (PFS). In some embodiments, the administration increasesoverall survival (OS).

In some embodiments, the administration can reduce free B7-H1 levels byat least 80%. In some embodiments, the administration can reduce freeB7-H1 levels by at least 90%. In some embodiments, the administrationcan reduce free B7-H1 levels by at least 95%. In some embodiments, theadministration can reduce free B7-H1 levels by at least 99%. In someembodiments, the administration can reduce the rate of increase in B7-H1levels.

In some embodiments, the tumor is a solid tumor. In some embodiments,the solid tumor is melanoma, renal cell carcinoma, non-small cell lungcancer, or colorectal cancer. In some embodiments, the tumor ismelanoma. In some embodiments, the tumor is renal cell carcinoma. Insome embodiments, the tumor is non-small cell lung cancer. In someembodiments, the tumor is colorectal cancer.

In some embodiments, the tumor is NSCLC (Squamous cell carcinoma),hepatocellular cancer (HCC), triple-negative breast cancer (TNBC),pancreatic cancer, GI cancer, melanoma, uveal melanoma, or squamous cellcarcinoma of the head and neck (SCCHN). In some embodiments, the tumoris NSCLC (Squamous cell carcinoma). In some embodiments, the tumor isHCC. In some embodiments, the tumor is TNBC. In some embodiments, thetumor is pancreatic cancer. In some embodiments, the tumor is GI cancer.In some embodiments, the tumor is melanoma. In some embodiments, thetumor is uveal melanoma. In some embodiments, the tumor is SCCHN.

In some embodiments, the tumor is melanoma, renal cell carcinoma,non-small cell lung cancer (squamous cell), non-small cell lung cancer(non-squamous cell), colorectal cancer, HCC, TNBC, pancreatic cancer, GIcancer, uveal melanoma, or SCCHN.

In some embodiments, the tumor is refractory to at least onechemotherapeutic agent. In some embodiments, the chemotherapeutic agentis Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin,Bevacizumab, Erlotinib, or Pemetrexed.

In some embodiments, the patient has an Eastern Cooperative OncologyGroup (ECOG) performance status of 0 or 1.

In some embodiments, the administration is by intravenous infusion. Insome embodiments, the administration occurs over about an hour.

In certain aspects of the provided methods, administration of MEDI4736or an antigen-binding fragment thereof results in the pharmacokineticprofiles as shown in FIGS. 4-6.

In certain aspects of the provided methods, administration of MEDI4736or an antigen-binding fragment thereof results in in the pharmacokineticprofiles obtained in Example 2.

In certain aspects of the provided methods, administration of MEDI4736or an antigen-binding fragment thereof results in treatment of a tumoras shown in FIGS. 7-9.

In certain aspects of the provided methods, administration of MEDI4736or an antigen-binding fragment thereof results in treatment of a tumoras shown in Example 2.

The invention also provides a method of quantifying soluble B7-H1 asshown in Example 3.

In another aspect, the invention provides a method of treating a patientidentified as having a B7-H1-expressing tumor, the method involvingadministering MEDI4736 or an antigen binding fragment thereof to a humanpatient, where the patient is identified by detecting B7-H1 expressionin one or more tumor cells.

In another aspect, the invention provides a method of increasing theefficacy of a MEDI4736 cancer treatment involving administering MEDI4736to a human patient identified as having tumor cells expressing B7-H1.

In various embodiments of the previous aspects, B7-H1 is detected usingimmunohistochemistry, for example, in formalin fixed and paraffinembedded tumor samples. In other embodiments, at least 25% of the tumorcells contain B7-H1-membrane staining. In other embodiments, there is a40% or 50% objective response rate in patients identified as having aB7-H1-expressing tumor. In other embodiments, the tumor is a melanoma,renal cell carcinoma, non-small cell lung cancer, pancreaticadenocarcinoma, gastroesophageal carcinoma, uveal melanoma, triplenegative breast carcinoma, hepatocellular carcinoma, squamous cellcarcinoma, or colorectal cancer. In other embodiments, the tumor is anon-small cell lung cancer (e.g., squamous cell carcinoma or anon-squamous cell carcinoma). In other embodiments, the tumor is asquamous cell carcinoma of the head and neck. In other embodiments,about 0.1, about 0.3, about 1, about 3, about 10, or about 15 mg/kgMEDI4736 or an antigen-binding fragment thereof is administered. Inparticular embodiments, the administration is repeated about ever 14 or21 days. In other embodiments, at least two, three, four, or five dosesof MEDI4736 is administered.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 shows the timeline of treatment with MEDI4736 administeredintravenously (IV) every two weeks (Q2W). Immune-related responsecriteria (irRC) are measured after weeks 6, 12, and 16 and then every 8weeks.

FIG. 2A shows the study flow diagram for the dose-expansion anddose-escalation portions of the study. The dose expansion portion of thestudy is conducted using a two-week dosing schedule (Q2W) and athree-week dosing schedule (Q3W). Patients with non-small cell lungcancer (NSCLC), melanoma, and other tumors are evaluated in theescalation portion of the study; FIG. 2B shows the tumor types in theexpansion.

FIG. 3 shows the baseline demographics of subjects treated with 0.1,0.3, 1, 3, 10, or 15 mg/kg of MED4736 in the dose-escalation study.

FIG. 4 shows a summary of the pharmacokinetic data obtained afteradministering MEDI4736 (Q2W) at 0.1 mg/kg or 0.3 mg/kg during thedose-escalation phase of the study. “AUC”=area under the curve;“Cmax”=maximum observed concentration (Panel A).

FIG. 5 shows the concentration of MEDI4736 over time that was observedin patients receiving 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kgMEDI4736 (Q2W) during the dose-escalation phase of the study.

FIG. 6 shows the target engagement over time that was observed inpatients receiving 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kgMEDI4736 (Q2W) during the dose-escalation phase of the study.“LLOQ”=lower limit of quantitation.

FIG. 7 shows the clinical activity of MEDI4736 observed in patients withnon-small cell lung cancer (NSCLC), melanoma, or colorectal cancer (CRC)receiving 0.1 mg/kg, 0.3 mg/kg, or 1 mg/kg MEDI4736. Best responses arecharacterized as stable disease (SD), progressive disease (PD), partialresponse (PR), or not evaluable (NE)

FIG. 8 shows the effect of MEDI4736 on tumor size in patients receiving0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 10 mg/kg or 15 mg/kg MEDI4736.

FIG. 9 shows effect of 10 mg/kg MEDI4736 on NSCLC tumors.

FIG. 10 shows the percent change of tumor size from baseline for alldose levels for NSCLC (Non-squamous and squamous).

FIG. 11 shows the percent change of tumor size from baseline for alldose levels for advanced cutaneous melanoma.

FIG. 12 shows the percent change of tumor size from baseline for SCCHNpatients treated with 10 mg/kg MEDI4736 2QW.

FIG. 13 shows the percent change of tumor size from baseline forpancreatic adenocarcinoma patients treated with 10 mg/kg MEDI4736 2QW(Panel A); The best change in tumor size from baseline is shown in PanelB.

FIGS. 14A&B shows the percent change of tumor size from baseline forgastroesophageal cancer patients treated with 10 mg/kg MEDI4736 2QW(FIG. 14A). The best change in tumor size from baseline is shown in FIG.14B.

FIG. 15 shows the percent change of tumor size from baseline forhepatocellular carcinoma (HCC) patients treated with 10 mg/kg MEDI47362QW. The best change in tumor size from baseline is shown in Panel B.

FIG. 16 shows the percent change of tumor size from baseline for triplenegative breast cancer (TNBC) patients treated with 10 mg/kg MEDI47362QW.

FIG. 17 shows the percent change of tumor size from baseline for uvealmelanoma patients treated with 10 mg/kg MEDI4736 2QW.

FIG. 18A shows a comparison of the percent change in tumor size frombaseline for NSCLC patients treated with 10 mg/kg MEDI4736 2QW evaluablefor 2 scans. The plot shows patients with PD-L1 Positive tumors, PD-L1Negative tumors and patients whose PD-L1 tumor status was not available.Patients that were identified as smokers are shown with a star. The ORR(confirmed CR+PR) for all patients was 3.7%. The ORR rate for PD-L1+patients was 10%.

FIG. 18B shows a comparison of the percent change in tumor size frombaseline for NSCLC patients treated with all dose levels of MEDI4736 2QWevaluable for 1 scan. The plot shows patients with PD-L1 Positivetumors, PD-L1 Negative tumors and patients whose PD-L1 tumor status wasnot available. Patients that were identified as smokers are shown with astar. The ORR (confirmed CR+PR) for all confirmed patients was 4.3% (ORRfor all unconfirmed patients was 8.5%). The ORR rate for PD-L1+patientswas 8.3%.

FIG. 19 shows the change in tumor size for 6 tumor types in theEscalation Phase.

FIG. 20 shows the response of a pancreatic cancer patient treated with10 mg/kg Q2W MEDI4736. Panel A shows the initial screening and Panel Bshows the subject at week 6.

FIG. 21 shows response in a female patient with SCCHN before (Panel A)and after (Panel B) treatment with 2 infusions of 10 mg/kg MEDI4736.

FIG. 22 shows staining of PD-L1 in Subject tissue of NSCLC (freshbiopsy).

FIG. 23 shows staining of PD-L1 in Subject tissue (fresh biopsy)indicating neoplastic cells and immune cells.

FIG. 24 shows staining of PD-L1 in Subject tissue) indicating neoplasticcells and immune and endothelial cells.

FIGS. 25A-C show the response in the patients to treatment of MEDI4736relative to their PD-L1 tumor status. FIG. 25A is a spider plot showingtumor size following MEDI4736 treatment in Non-squamous and SquamousNSCLC. FIG. 25B is a spider plot showing tumor size following MEDI4736treatment in PD-L1 positive and PD-L1 negative NSCLC tumors. FIG. 25C isa waterfall plot showing change in tumor size in PD-L1 positive andPD-L1 negative NSCLC patients.

DETAILED DESCRIPTION

It is to be noted that the term “a” or “an” entity refers to one or moreof that entity; for example, “an anti-B7-H1 antibody” is understood torepresent one or more anti-B7-H1 antibodies. As such, the terms “a” (or“an”), “one or more,” and “at least one” can be used interchangeablyherein.

Provided herein are methods for treating tumors. The methods providedinclude administering an effective amount of MEDI4736 or anantigen-binding fragment thereof.

Information regarding MEDI4736 (or fragments thereof) for use in themethods provided herein can be found in International ApplicationPublication No. WO 2011/066389 A1, the disclosure of which isincorporated herein by reference in its entirety. The fragmentcrystallizable (Fc) domain of MEDI4736 contains a triple mutation in theconstant domain of the IgG1 heavy chain that reduces binding to thecomplement component C1q and the Fcγ receptors responsible for mediatingantibody-dependent cell-mediated cytotoxicity (ADCC). MEDI4736 isselective for B7-H1 and blocks the binding of B7-H1 to the PD-1 and CD80receptors. MEDI4736 can relieve B7-H1-mediated suppression of humanT-cell activation in vitro and inhibits tumor growth in a xenograftmodel via a T-cell dependent mechanism.

MEDI4736 and antigen-binding fragments thereof for use in the methodsprovided herein comprises a heavy chain and a light chain or a heavychain variable region and a light chain variable region. In a specificaspect, MEDI4736 or an antigen-binding fragment thereof for use in themethods provided herein comprises a light chain variable regioncomprising the amino acid sequence of SEQ ID NO:1 and a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO:2. In aspecific aspect, MEDI4736 or an antigen-binding fragment thereof for usein the methods provided herein comprises a heavy chain variable regionand a light chain variable region, wherein the heavy chain variableregion comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQID NOs:3-5, and wherein the light chain variable region comprises theKabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:6-8. Those ofordinary skill in the art would easily be able to identifyChothia-defined, Abm-defined or other CDR definitions known to those ofordinary skill in the art. In a specific aspect, MEDI4736 or anantigen-binding fragment thereof for use in the methods provided hereincomprises the variable heavy chain and variable light chain CDRsequences of the 2.14H9OPT antibody as disclosed in WO 2011/066389 A1,which is herein incorporated by reference in its entirety.

In certain aspects, a patient presenting with a tumor is administeredMEDI4736 or an antigen-binding fragment thereof. MEDI4736 or anantigen-binding fragment thereof can be administered only once orinfrequently while still providing benefit to the patient. In furtheraspects the patient is administered additional follow-on doses.Follow-on doses can be administered at various time intervals dependingon the patient's age, weight, clinical assessment, tumor burden, and/orother factors, including the judgment of the attending physician.

The intervals between doses can be every two weeks. The interval betweendoses can be every three weeks. The intervals between doses can be everytwo months (e.g., during a maintenance phase).

The dosing intervals can also be about every 14 days or about every 21days. In some embodiments, “about” every 14 days or “about” every 21days indicates 14 days+/−2 days or 21 days+/−2 days. In someembodiments, administration of MEDI4736 is about every 14 to 21 days.

In some embodiments, at least two doses of MEDI4736 or anantigen-binding fragment thereof are administered to the patient. Insome embodiments, at least three doses, at least four doses, at leastfive doses, at least six doses, at least seven doses, at least eightdoses, at least nine doses, at least ten doses, or at least fifteendoses or more can be administered to the patient. In some embodiments,MEDI4736 or an antigen-binding fragment thereof is administered over atwo-week treatment period, over a four-week treatment period, over asix-week treatment period, over an eight-week treatment period, over atwelve-week treatment period, over a twenty-four-week treatment period,or over a one-year or more treatment period. In some embodiments,MEDI4736 or an antigen-binding fragment thereof is administered over athree-week treatment period, a six-week treatment period, over anine-week treatment period, over a twelve-week treatment period, over atwenty-four-week treatment period, or over a one-year or more treatmentperiod. In some embodiments, MEDI4736 or an antigen-binding fragmentthereof is administered over a two-month treatment period, over afour-month treatment period, or over a six-month or more treatmentperiod (e.g., during a maintenance phase).

The amount of MEDI4736 or an antigen-binding fragment thereof to beadministered to the patient will depend on various parameters such asthe patient's age, weight, clinical assessment, tumor burden and/orother factors, including the judgment of the attending physician.

In certain aspects the patient is administered one or more doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 0.1 mg/kg. In certain aspects the patient is administered one ormore doses of MEDI4736 or an antigen-binding fragment thereof whereinthe dose is about 0.3 mg/kg. In certain aspects the patient isadministered one or more doses of MEDI4736 or an antigen-bindingfragment thereof wherein the dose is about 1 mg/kg. In certain aspectsthe patient is administered one or more doses of MEDI4736 or anantigen-binding fragment thereof wherein the dose is about 3 mg/kg. Incertain aspects the patient is administered one or more doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 10 mg/kg. In certain aspects the patient is administered one ormore doses of MEDI4736 or an antigen-binding fragment thereof whereinthe dose is about 15 mg/kg.

In certain aspects the patient is administered at least two doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 0.1 mg/kg. In certain aspects the patient is administered at leasttwo doses of MEDI4736 or an antigen-binding fragment thereof wherein thedose is about 0.3 mg/kg. In certain aspects the patient is administeredat least two doses of MEDI4736 or an antigen-binding fragment thereofwherein the dose is about 1 mg/kg. In certain aspects the patient isadministered at least two doses of MEDI4736 or an antigen-bindingfragment thereof wherein the dose is about 3 mg/kg. In certain aspectsthe patient is administered at least two doses of MEDI4736 or anantigen-binding fragment thereof wherein the dose is about 10 mg/kg. Incertain aspects the patient is administered at least two doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 15 mg/kg. In some embodiments, the at least two doses areadministered about two weeks apart. In some embodiments, the at leasttwo doses are administered about three weeks apart.

In certain aspects the patient is administered at least three doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 0.1 mg/kg. In certain aspects the patient is administered at leastthree doses of MEDI4736 or an antigen-binding fragment thereof whereinthe dose is about 0.3 mg/kg. In certain aspects the patient isadministered at least three doses of MEDI4736 or an antigen-bindingfragment thereof wherein the dose is about 1 mg/kg. In certain aspectsthe patient is administered at least three doses of MEDI4736 or anantigen-binding fragment thereof wherein the dose is about 3 mg/kg. Incertain aspects the patient is administered at least three doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 10 mg/kg. In certain aspects the patient is administered at leastthree doses of MEDI4736 or an antigen-binding fragment thereof whereinthe dose is about 15 mg/kg. In some embodiments, the at least threedoses are administered about two weeks apart. In some embodiment, the atleast three doses are administered about three weeks apart.

In certain aspects, administration of MEDI4736 or an antigen-bindingfragment thereof according to the methods provided herein is throughparenteral administration. For example, MEDI4736 or an antigen-bindingfragment thereof can be administered by intravenous infusion or bysubcutaneous injection. In some embodiments, the administration is byintravenous infusion.

In certain aspects, MEDI4736 or an antigen-binding fragment thereof isadministered according to the methods provided herein in combination orin conjunction with additional cancer therapies. Such therapies include,without limitation, chemotherapeutic agents such as Vemurafenib,Erlotinib, Afatinib, Cetuximab, Carboplatin, Bevacizumab, Erlotinib, orPemetrexed, or other chemotherapeutic agents, as well radiation or anyother anti-cancer treatments.

The methods provided herein can decrease tumor size, retard tumor growthor maintain a steady state. In certain aspects the reduction in tumorsize can be significant based on appropriate statistical analyses. Areduction in tumor size can be measured by comparison to the size ofpatient's tumor at baseline, against an expected tumor size, against anexpected tumor size based on a large patient population, or against thetumor size of a control population. In certain aspects provided herein,the administration of MEDI4736 can reduce a tumor size by at least 25%.In certain aspects provided herein, the administration of MEDI4736 canreduce a tumor size by at least 25% within about 6 weeks of the firsttreatment. In certain aspects provided herein, the administration ofMEDI4736 can reduce a tumor size by at least 50%. In certain aspectsprovided herein, the administration of MEDI4736 can reduce a tumor sizeby at least 50% within about 10 weeks of the first treatment. In certainaspects provided herein, the administration of MEDI4736 can reduce atumor size by at least 75%. In certain aspects provided herein, theadministration of MEDI4736 can reduce a tumor size by at least 75%within about 10 weeks of the first treatment.

In certain aspects, use of the methods provided herein, i.e.,administration of MEDI4736 or an antigen-binding fragment thereof candecrease tumor size within 6 weeks, within 7 weeks, within 8 weeks,within 9 weeks, within 10 weeks, within 12 weeks, within 16 weeks,within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks,within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, orwithin 52 weeks of the first treatment.

In some embodiments, administration of 1 mg/kg of MEDI4736 or anantigen-binding fragment thereof (e.g., at least one dose, at least twodoses, at least three doses, at least four doses, at least five doses,at least six doses, at least seven doses, at least eight doses, at leastnine doses, at least ten doses, or more every two weeks or every threeweeks) can be sufficient to reduce tumor size. However, as providedherein, larger doses can also be administered, for example, to optimizeefficacy, number of doses necessary, or certain pharmacokineticparameters.

The methods provided herein can decrease or retard tumor growth. In someaspects the reduction or retardation can be statistically significant. Areduction in tumor growth can be measured by comparison to the growth ofpatient's tumor at baseline, against an expected tumor growth, againstan expected tumor growth based on a large patient population, or againstthe tumor growth of a control population.

In certain aspects, a patient achieves disease control (DC). Diseasecontrol can be a complete response (CR), partial response (PR), orstable disease (SD).

A “complete response” (CR) refers to the disappearance of all lesions,whether measurable or not, and no new lesions. Confirmation can beobtained using a repeat, consecutive assessment no less than four weeksfrom the date of first documentation. New, non-measurable lesionspreclude CR.

A “partial response” (PR) refers to a decrease in tumor burden ≥50%relative to baseline. Confirmation can be obtained using a consecutiverepeat assessment at least 4 weeks from the date of first documentation

“Progressive disease” (PD) refers to an increase in tumor burden ≥25%relative to the minimum recorded (nadir). Confirmation can be obtainedby a consecutive repeat assessment at least 4 weeks from the date offirst documentation. New, non-measurable lesions do not define PD.

“Stable disease” (SD) refers to not meeting the criteria for CR, PR, orPD.

In certain aspects, administration of MEDI4736 or an antigen-bindingfragment thereof can increase progression-free survival (PFS).

In certain aspects, administration of MEDI4736 or an antigen-bindingfragment thereof can increase overall survival (OS).

In certain aspects, the patient has a particular type of tumor. In someembodiments, the tumor is a solid tumor. In some embodiments, the tumoris a melanoma, a renal cell carcinoma, a non-small cell lung cancer(e.g., squamous or adenocarcinoma), or a colorectal cancer. In someembodiments, the tumor is a melanoma, a non-small cell lung cancer(e.g., squamous or adenocarcinoma), or a colorectal cancer. In someembodiments, the tumor is melanoma. In some embodiments, the tumor isrenal cell carcinoma. In some embodiments, the tumor is non-small celllung cancer. In some embodiments, the tumor is colorectal cancer.

In some embodiments, the tumor is NSCLC (Squamous cell carcinoma),hepatocellular cancer (HCC), triple-negative breast cancer (TNBC),pancreatic cancer, GI cancer, melanoma, uveal melanoma, or squamous cellcarcinoma of the head and neck (SCCHN). In some embodiments, the tumoris NSCLC (Squamous cell carcinoma). In some embodiments, the tumor isHCC. In some embodiments, the tumor is TNBC. In some embodiments, thetumor is pancreatic cancer. In some embodiments, the tumor is GI cancer.In some embodiments, the tumor is melanoma. In some embodiments, thetumor is uveal melanoma. In some embodiments, the tumor is SCCHN.

In some embodiments, the tumor is melanoma, renal cell carcinoma,non-small cell lung cancer (squamous cell), non-small cell lung cancer(non-squamous cell), colorectal cancer, HCC, TNBC, pancreatic cancer, GIcancer, uveal melanoma, or SCCHN.

In some embodiments, the patient has previously received treatment withat least one chemotherapeutic agent. In some embodiments, the patienthas previously received treatment with at least two chemotherapeuticagents. The chemotherapeutic agent can be, for example, and withoutlimitation, Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin,Bevacizumab, Erlotinib, and/or Pemetrexed.

In some embodiments, the tumor is refractory or resistant to at leastone chemotherapeutic agent. In some embodiments, the tumor is refractoryor resistant to at least two chemotherapeutic agents. The tumor can berefractory or resistant to one or more of, for example, and withoutlimitation, Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin,Bevacizumab, Erlotinib, and/or Pemetrexed.

In some embodiments, the patient has an Eastern Cooperative OncologyGroup (ECOG) (Oken M M, et al. Am. J. Clin. Oncol. 5: 649-55 (1982))performance status of 0 or 1 prior to the administration of MEDI4736 oran antigen-binding fragment thereof.

According to the methods provided herein, administration of MEDI4736 oran antigen-binding fragment thereof can result in desirablepharmacokinetic parameters. Total drug exposure can be estimated usingthe “area under the curve” (AUC). “AUC (tau)” refers to AUC until theend of the dosing period, whereas “AUC (inf)” refers to the AUC untilinfinite time. The administration can produce AUC (tau) of about 100 toabout 2,500 d·μg/mL. The administration can produce a maximum observedconcentration (Cmax) of about 15 to about 350 μg/mL. The half-life ofthe MEDI4736 or the antigen-binding fragment thereof can be about 5 toabout 25 days. In addition, the clearance of the MEDI4736 or theantigen-binding fragment thereof can be about 1-10 ml/day/kg.

As provided herein, MEDI4736 is an isolated antibody or anantigen-binding fragment thereof that specifically binds to B7-H1,comprising a VH CDR1 having the amino acid sequence of SEQ ID NO: 3; aVH CDR2 having the amino acid sequence of SEQ ID NO: 4; a VH CDR3 havingthe amino acid sequence of SEQ ID NO: 5; a VL CDR1 having the amino acidsequence of SEQ ID NO: 6; a VL CDR2 having the amino acid sequence ofSEQ ID NO: 7; a VL CDR3 having the amino acid sequence of SEQ ID NO: 8.Also as provided herein, MEDI4736 is also an isolated antibody or anantigen-binding fragment thereof that specifically binds to B7-H1comprising a VL having the amino acid sequence of SEQ ID NO: 1; and a VHhaving the amino acid sequence of SEQ ID NO: 2. MEDI4736 or anantigen-binding fragment thereof can also decrease free B7-H1 levels.Free B7-H1 refers to B7-H1 that is not bound (e.g., by MEDI4736). Insome embodiments, B7-H1 levels are reduced by at least 80%. In someembodiments, B7-H1 levels are reduced by at least 90%. In someembodiments, B7-H1 levels are reduced by at least 95%. In someembodiments, B7-H1 levels are reduced by at least 99%. In someembodiments, B7-H1 levels are eliminated following administration ofMEDI4736 or an antigen-binding fragment thereof. In some embodiments,administration of MEDI4736 or an antigen-binding fragment thereofreduces the rate of increase of B7-H1 levels as compared, e.g., to therate of increase of B7-H1 levels prior to the administration of MEDI4736or an antigen-binding fragment thereof.

Advantageously, the methods of administration provided herein alsominimize anti-drug antibody responses provided herein. Accordingly, insome embodiments, administration of MEDI4736 or an antigen-bindingfragment thereof to a patient in need of treatment with an anti-B7-H1,anti-B7-1, or anti-PD-1, minimizes the anti-drug antibodies produced bythe patient. In some embodiments, anti-drug antibodies do not impactMEDI4736 exposure in patients treated with MEDI4736.

EXAMPLES Example 1: Patients and Methods

(a) Subjects

Subjects in this study were required to be 18 years of age or older withadvanced malignant melanoma, renal cell carcinoma (RCC), non-small celllung cancer (NSCLC), or colorectal cancer (CRC) refractory to standardtherapy or for which no standard therapy exists. Subjects in thedose-expansion phase of the study will be adults with advanced malignantmelanoma, NSCLC, or CRC refractory to standard therapy or for which nostandard therapy exists. Additional subjects in the dose-expansion phasehad NSCLC (Squamous cell carcinoma), hepatocellular cancer (HCC),triple-negative breast cancer (TNBC), pancreatic cancer, GI cancer,melanoma, uveal melanoma, or Squamous cell carcinoma of the head andneck (SCCHN). The cancers must be histologically- or cytologicallyconfirmed. The subjects are required to have an Eastern CooperativeOncology Group (ECOG) status of 0 or 1 as well as adequate organ andmarrow function. Adequate organ and marrow function was defined as:hemoglobin ≥9 g/dL; absolute neutrophil count ≥1,500/mm³; lymphocytecount ≥800/mm³; platelet count ≥100,000/mm³; aspartate aminotransferase(AST) and alanine aminotransferase (ALT) ≤2.5×institutional upper limitof normal (ULN); bilirubin ≤1.5×ULN except in the case of subjects withdocumented or suspected Gilbert's disease (for these subjects, bilirubinmust be ≤5×ULN); creatinine clearance ≥50 mL/min as determined by theCockcroft-Gault equation or by 24-hour urine collection fordetermination of creatinine clearance.

Subjects are not able to participate if they have active autoimmunedisease, prior anti-PD-1 or anti-PD-L1 therapy, or prior severe orpersistent immune-related adverse events (irAE). Subjects are notpermitted to have any concurrent chemotherapy, immunotherapy, biologicor hormonal therapy for cancer treatment, but concurrent use of hormonesfor non-cancer related conditions (e.g., insulin for diabetes andhormone replacement therapy) are allowed.

(b) Design of the Study

The study is a multicenter, open-label, Phase 1, first-time-in-human,dose-escalation and dose-expansion study in which multiple doses ofMEDI4736 are administered via intravenous (IV) infusion to cancerpatients. MEDI4736 was administered at 0.1, 0.3, 1, 3, 10, and 15 mg/kgdoses. The study flow diagram is shown in FIG. 1. The first day ofdosing is considered Day 1, and disease assessment takes place after 6,12, and 16 weeks, and then every 8 weeks.

A dose-escalation was performed with administration every 2 weeks (Q2W)(+/−2 days) to different cohorts with doses of 0.1, 0.3, 1, 3, and 10mg/kg doses.

A separate dose-escalation was performed with administration every 3weeks (Q3W) at 15 mg/kg. An expansion phase is then conducted using themaximum tolerated dose (MTD) or optimal biological dose (OBD) identifiedin the dose-escalation.

A dose of 15 mg/kg Q2W may also be performed.

Dose Escalation

In the dose-escalation phase, the first dose of MEDI4736 wasadministered to all subjects in the first cohort as a 0.1 mg/kg infusiongiven over 4 hours. Subsequent infusions (2nd and 3rd doses, etc.) forthe first cohort were given over 60 minutes Q2W. The doses forsubsequent cohorts were 0.3, 1.0, 3.0, or 10 mg/kg, administered as a60-minute IV infusion Q2W. A summary of the dose cohorts for the initialdose escalation is provided in Table 1 below. Additional doses of 15mg/kg were also administered at Q3W.

TABLE 1 Q2W Dosing Regimen Dose Number Cohort Subjects Dosing Regimen 13-6 0.1 mg/kg as a 4-hour IV infusion for the initial dose, and then as60-minute IV infusion once every 2 weeks 2 3-6 0.3 mg/kg as a 60-minuteIV infusion once every 2 weeks 3 3-6 1.0 mg/kg as a 60-minute IVinfusion once every 2 weeks 4 3-6 3.0 mg/kg as a 60-minute IV infusiononce every 2 weeks 5 3-6 10 mg/kg as a 60-minute IV infusion once every2 weeks 6 3-6 15 mg/kg as a 60-minute IV infusion once every 3 weeks

With the completion of all cohorts in the Q2W dose escalation regimen, aseparate dose escalation using the Q3W regimen begins and proceeds to adose of up to 15 mg/kg Q3W based on available safety,PK/pharmacodynamics, and clinical data. The starting dose in the Q3Wescalation is the equivalent dosing rate (in average mg/kg/week) to theoptimal biological dose (OBD) (or highest dose tested if an OBD is notidentified).

Subjects in the dose-escalation phase continue treatment until confirmedPD, initiation of alternative cancer therapy, unacceptable toxicity, orother reasons to discontinue treatment occur. In those subjectsachieving confirmed disease control (DC), treatment may continue until 6months past the date of confirmed DC. DC will include stable disease(SD) with a duration of 3 or more months, partial response (PR), andcomplete response (CR).

Dose Expansion

Following the completion of dose escalation at Q2W and Q3W, the doseregimen for the expansion phase is selected. Subjects enrolled in thedose expansion cohorts will receive MEDI4736 at the maximum tolerateddose (MTD), optimal biological dose (OBD), or the highest dose evaluatedduring dose escalation if no MTD or OBD is determined, given as an IVinfusion at the selected dose and frequency. Subjects who achievedisease control (DC) will continue treatment and then enter themaintenance period. Upon evidence of progressive disease (PD) at anytime during the maintenance period, MEDI4736 will be re-administered asan IV infusion until confirmed PD or other reason to discontinueMEDI4736.

Maintenance Period

Subjects who achieve disease control (DC) during the escalation orexpansion phases enter the maintenance period in which treatment cancontinue until six months past the date of confirmed DC.

During the maintenance period, MEDI4736 is administered as an IVinfusion every 2 months for 6 months. Physical examination of subjectswill be performed at months 2, 4, and 6. After a 6-month period of every2-month dosing, MEDI4736 is discontinued. Upon evidence of progressivedisease (PD), MEDI4736 is re-administered as an IV infusion at a Q2W orQ3W schedule until confirmed PD, initiation of alternative cancertherapy, unacceptable toxicity, withdrawal of consent, or other reasonto discontinue treatment, for a maximum of 2 years.

(c) Phamacokinetic, Anti-Tumor and Safety Assessments

Measurement of MEDI4736 concentrations in serum were performed using avalidated immunoassay during the Q2W dose-escalation phase. Bloodsamples for pharmacokinetic assessment, as well as for soluble B7-H1(sB7-H1) concentrations, were collected according to the followingschedules during the Q2W dose-escalation phase:

-   -   First dose: Day 1 predose, end of infusion (EOI), and 3 hours        after EOI, and Days 2, 3, 5, and 10 (+/−1 day). An additional        sample at 2 hours after the start of the infusion was taken        during the first study subject's initial, 4-hour infusion.    -   Second dose: Predose, EOI, 3 hours after EOI, and Day 8.    -   Subsequent even-numbered doses only: Predose and EOI.    -   Upon discontinuation or last dose, a pharmacokinetic (PK) sample        should be drawn at 14 days, 30 days, 2 and 3 months after last        dose.

For Q3W dosing, the pharmacokinetic assessments are performed at thesame schedule as Q2W dosing except that a blood sample is also collectedon Day 15 after the first dose. During the dose-expansion phase,pharmacokinetic assessments are performed every two months (Day 1predose and EOI). In addition, upon discontinuation or last dose, apharmacokinetic (PK) sample is drawn at 14 days, 30 days, 2 months, and3 months after the last dose. During the maintenance phase,pharmacokinetic assessments and evaluations of sB7-H1 are performed onDays 14 and 30 (+/−3 days), and at months 2, 4, and 6 (+/−1 week).

The presence of anti-drug antibodies (ADA) was assessed (and willcontinue to be assessed) on Day 1 (preinfusion) and at all dosesfollowing dose 2 during the Q2W dose-escalation phase. ADA will beassessed according to the same schedule in the Q3W dose-escalation anddose-expansion phases. During the maintenance phase, ADA will beassessed at month 6 (+/−1 week).

Tumor assessments were performed (and will continue to be performed)during screening (day-28 to day-1) and at week 7 in the Q2Wdose-escalation phase. Tumor assessments are performed with the sametiming in the Q3W dose-escalation phase and the dose-expansion phase.Tumor assessments can include the following evaluations: physicalexamination (with photograph and measurement of skin lesions asapplicable), CT, or MRI scan of the chest, abdomen, and pelvis, and CTor MRI scan of the brain. Computed tomography or MRI scan of the brainis performed only at screening or if the subject is neurologicallysymptomatic. During the maintenance phase, tumor assessments areperformed at months 2, 4, and 6 (+/−1 week).

During the expansion phase, tumor biopsies are also performed duringscreening (day-28 to day-1) and at week 7.

Assessments of anti-tumor activity are based on the immune-relatedobjective response rate (ORR), immune-related disease control rate(DCR), immune-related duration of response (DR), immune-relatedprogression-free survival (PFS), and overall survival (OS).Immune-related response criteria (Wolchok et al., Clin Cancer Res.15:7412-20 (2009)) were used to determine tumor response.

The ORR is defined as the proportion of subjects with confirmed completeresponse (CR) or confirmed partial response (PR). Confirmed responsesare those that persist on repeat imaging study ≥4 weeks after theinitial documentation of response. The DCR is defined as the proportionof subjects with CR, PR or stable disease (SD) (subjects achieving SDwill be included in the DCR if they maintain SD for ≥3 months). The 95%confidence interval (CI) of ORR and DCR is estimated using the exactprobability method. The duration of response (DR) is the duration fromthe first documentation of objective response to the first documenteddisease progression. Progression-free survival (PFS) is measured fromthe start of treatment with MEDI4736 until the documentation ofconfirmed immune-related disease progression or death due to any cause,whichever occurs first. Overall survival (OS) is the time from the startof treatment with MEDI4736 until death.

Adverse events are monitored following administration of MEDI4736. Otherassessments include physical examination, vital sign monitoring, andlaboratory measurements.

Example 2: Results

(a) Enrollment and Baseline Characteristics

The baseline characteristics of the subjects administered 0.1, 0.3, or 1mg/kg MEDI4736 in the Q2W dose-escalation phase are provided in Table 2below. In addition, 245 patients have been treated with 10 mg/kg Q2W and6 patients have been treated with 15 mg/kg Q3W.

TABLE 2 Demographics for Q2W dosing 0.1 mg/kg 0.3 mg/kg 1.0 mg/kg TotalCharacteristic (n = 4) (n = 4) (n = 3) (N = 11) Mean Age (yrs) 58.5 68.065.3 63.8 (46-65) (65-71) (43-77) (43-77) Gender 2/2 3/1 1/2 6/5(male/female) ECOG 1 at 2 1 2 5 baseline (n) ECOG 0 at 2 3 1 6 baseline(n) Mean number of 9.8 (5-17) 5.8 (4-9) 6.0 (1-10) 7.3 (1-17) priorcancer treatments (range) Colorectal tumor 0 1 0 1 (n) Melanoma (n) 1 01 2 NSCLC (n) 3 3 2 8

The baseline characteristics of the subjects administered 0.1, 0.3, 1,3, 10, or 15 mg/kg MEDI4736 in the Q2W and Q3W dose-escalation phasesare provided in FIG. 3.

(b) Pharmacokinetics

The pharmacokinetic data resulting from administration of MEDI4736 at0.1 and 0.3 mg/kg in the Q2W dose-escalation phase is summarized in FIG.4. MEDI4736 exhibited a non-linear PK at lower doses, but a linear PKwith doses ≥1.0 mg/kg Q2W. See FIG. 5. MEDI4736 also showed adose-dependent increase in target engagement (FIG. 6), consistent withbinding of MEDI4736 with B7-H1. Based on calculations using pK data andmeasurements of soluble B7-H1, significant target occupancy was achievedwith doses ≥0.3 mg/kg Q2W, and near complete saturation is expected atdoses ≥3 mg/kg Q2W. See FIG. 6.

(c) Efficacy

Tumor shrinkage was observed at all dose levels, including in heavilypretreated patients and in patients with large tumor burdens. Activitywas apparent quickly (6 weeks) and was durable. Partial responses (PR)and stable disease (SD) were observed in patients receiving as little as0.1 mg/kg Q2W. See FIG. 7 and Table 3 below.

Number of % Change Dose Dosing Doses Best in Tumor (mg/kg) FrequencySubject ID Received Response Burden  0.1 Q2W 1056201004 25 SD    −47.6 0.1 Q2W 1056201006 11 PD      50.3  0.1 Q2W 1245501002  3 NE NE  0.1Q2W 1245501003  8 PD      55.8  0.3 Q2W 1094301002  5 PD +>100  0.3 Q2W1245501006 24 PR    −60.1  0.3 Q2W 1351901002  1 NE NE  0.3 Q2W1351901004 22 PR    −71.2  1 Q2W 1056201009 19 SD    −46.6  1 Q2W1094301003 18 PR    −83.3  1 Q2W 1351901007 17 PR    −76.8  3 Q2W1056201010  5 SD    −16.1  3 Q2W 1094301004  7 PD      38  3 Q2W1351901008  3 PD +>100 10 Q2W 1002501208  5 SD      32.4 10 Q2W1056201201  5 PD +>100 10 Q2W 1094301205 13 SD      9.3 10 Q2W1245501206  5 PD      60 10 Q2W 1351901209  3 PD      82 10 Q2W1371501207  2 PD      75.1 15 Q3W 1002501313  1 NA NA 15 Q3W 1056201213 4 SD      16.4 15 Q3W 1245501211  5 SD    −5 15 Q3W 1351901223  4 SD     10 15 Q3W 1371501297  2 NA NA 15 Q3W 1372001228  5 SD      0

In addition, tumor burdens decreased as must as 83% in patientsreceiving up to 10 mg/kg Q2W. See FIGS. 7-9. For instance, one NSCLCadenocarcinoma patient (1351901004) receiving 0.3 mg/kg showed a 31%decrease in tumor burden after 6 weeks and a 71% decrease in tumorburden after 23 weeks. Prophylactic steroids were used in one subjectand did not appear to affect clinical activity.

In the dose-expansion phase, clinical activity was initially observed insubjects with non-small cell lung cancer, melanoma, and pancreaticcancer. Stable disease (at 12 weeks) was observed in subjects withnon-small cell lung cancer (non-squamous), pancreatic cancer, GI cancer,melanoma, and squamous cell carcinoma of the head and neck.

The percent change of tumor size from baseline for all dose levels forNSCLC (Non-squamous and squamous) is shown in FIG. 10.

The percent change of tumor size from baseline for all dose levels foradvanced cutaneous melanoma is shown in FIG. 11.

The percent change of tumor size from baseline for SCCHN patientstreated with 10 mg/kg MEDI4736 2QW is shown in FIG. 12.

The percent change of tumor size from baseline for pancreaticadenocarcinoma patients treated with 10 mg/kg MEDI4736 2QW is shown inFIG. 13. There are 8 subjects with SD [41-108 days] or better. Of these,6 patients had ≥2 L of therapy prior to study enrollment. Seven of eightpatients with SD or better are PD-L1(−)(the other patient's PD-L1 statusis unknown).

The percent change of tumor size from baseline for gastroesophagealcancer patients treated with 10 mg/kg MEDI4736 2QW is shown in FIG. 14.There are 9 subjects with SD [35-174 days] or better. Of these, 6 had ≥2L of therapy prior to study enrollment. Three patients with SD or betterare PD-L1(−), 2 are PD-L1(+) and the rest are unknown.

The percent change of tumor size from baseline for hepatocellularcarcinoma (HCC) patients treated with 10 mg/kg MEDI4736 2QW is shown inFIG. 15. Of the 17 patients enrolled, all have received Sorafenibpreviously. Three are HBV(+), 2 are HCV(+) and the rest are HBV(−) &HCV(−). There are 5 subjects with SD [33-76 days] or better. Of these, 4of them have had ≥2 L of therapy prior to enrollment; 1 HBV(+); 4 HBV(−)& HCV(−). Three patients with SD or better are PD-L1(−) and the PD-L1status is unknown in the rest of these patients.

The percent change of tumor size from baseline for triple negativebreast cancer (TNBC) patients treated with 10 mg/kg MEDI4736 2QW isshown in FIG. 16.

The percent change of tumor size from baseline for uveal melanomapatients treated with 10 mg/kg MEDI4736 2QW is shown in FIG. 17.

A comparison of the percent change in tumor size from baseline for NSCLCpatients treated with 10 mg/kg MEDI4736 2QW evaluable for 2 scans isshown in FIG. 18A. The plot shows patients with PD-L1 Positive tumors,PD-L1 Negative tumors and patients whose PD-L1 tumor status was notavailable. Patients that were identified as smokers are shown with astar. The ORR (confirmed CR+PR) for all patients was 3.7%. The ORR ratefor PD-L1+patients was 10%.

A comparison of the percent change in tumor size from baseline for NSCLCpatients treated with all dose levels of MEDI4736 2QW evaluable for 1scan is shown in FIG. 18B. The plot shows patients with PD-L1 Positivetumors, PD-L1 Negative tumors and patients whose PD-L1 tumor status wasnot available. Patients that were identified as smokers are shown with astar. The ORR (confirmed CR+PR) for all confirmed patients was 4.3% (ORRfor all unconfirmed patients was 8.5%). The ORR rate for PD-L1+patientswas 8.3%.

The change in tumor size for 6 tumor types in the Escalation Phase areshown in FIG. 19.

The response of one patient in the Expansion Phase treated with 10 mg/kgMEDI4736 Q2W is shown in FIG. 20. In the upper left Panel, the patienttumor is marked. After week 6, the tumor has shrunk as shown in theupper right panel.

A dramatic effect of tumor regression in a patient with SCCHN (PD-L1⁺)after only two infusions of MEDI4736 (10 mg/kg Q2W) is shown in FIG. 21.

PD-L1 Staining

PD-L1 staining in tumor tissue from a panel of tumors was performed toassess level of PD-L1 in various tumors by IHC. The results are shown inTable 4.

TABLE 4 Tumor N Examined N PD-L1 Positive % Positive NSCLC - SCC 75 2229.3 NSCLC - Adeno 36 12 33.3 Small Cell LC 37 2 5.4 Breast - TN 42 1126.2 Head and Neck SCC 18 3 16.7 Gastric 20 3 15.0 HCC 40 4 10.0 UrinaryBladder 18 2 11.1 Uveal Melanoma 12 3 25.0 Mesothelioma 20 1 12.6Pancreas 25 1 3.6 CRC 32 1 3.1 RCC 20 0 0.0 Ovarian 48 0 0.0

The 10 mg/kg Q2W dose (N=245) was well tolerated. The most frequent SAEsare shown in Table 5 below:

TABLE 5 Q2W Q3W 0.1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 15 mg/kg N= 4 N = 4 N = 3 N = 3 N = 245 N = 6 Top 15 most frequent AE by preferredterm Fatigue 1 (25.0%) 2 (50.0%) 1 (33.3%) 0 (0.0%)  68 (27.8%) 3(50.0%) Dyspnoea 1 (25.0%) 2 (50.0%) 1 (33.3%)  1 (33.3%)  40 (16.3%) 1(16.7%) Nausea 0 (0.0%)  1 (25.0%) 2 (66.7%) 0 (0.0%)  37 (15.1%) 2(33.3%) Decreased Appetite 0 (0.0%)  1 (25.0%) 1 (33.3%) 0 (0.0%)  32(13.1%) 0 (0.0%)  Constipation 0 (0.0%)  1 (25.0%) 1 (33.3%)  1 (33.3%) 28 (11.4%) 0 (0.0%)  Pyrexia 0 (0.0%)  3 (75.0%) 0 (0.0%)   1 (33.3%)21 (8.6%) 2 (33.3%) Cough 1 (25.0%) 1 (25.0%) 0 (0.0%)   1 (33.3%) 20(8.2%) 3 (50.0%) Abdominal Pain 0 (0.0%)  1 (25.0%) 1 (33.3%) 0 (0.0%)20 (8.2%) 1 (16.7%) Diarrhoea 1 (25.0%) 2 (50.0%) 1 (33.3%) 0 (0.0%) 19(7.8%) 0 (0.0%)  Rash 1 (25.0%) 2 (50.0%) 2 (66.7%) 0 (0.0%) 18 (7.4%) 0(0.0%)  Vomiting 1 (25.0%) 1 (25.0%) 0 (0.0%)  0 (0.0%) 20 (8.2%) 1(16.7%) Dizziness 0 (0.0%)  1 (25.0%) 2 (66.7%) 0 (0.0%) 17 (6.9%) 0(0.0%)  Headache 1 (25.0%) 1 (25.0%) 1 (33.3%) 0 (0.0%) 16 (6.5%) 1(16.7%) Pruritus 0 (0.0%)  0 (0.0%)  1 (33.3%) 0 (0.0%) 19 (7.8%) 0(0.0%)  Chills 0 (0.0%)  1 (25.0%) 0 (0.0%)  0 (0.0%) 17 (6.9%) 0(0.0%) (d) Safety and Anti-Drug Antibodies

MEDI4736 was generally well tolerated. No pneumonitis, colitis (of anygrade), or hyperglycemia was observed. In addition, no treatment-relatedGrade ≥3 events were observed in the 0.1 to 3 mg/kg cohorts. Nodose-limiting toxicities were observed. A summary of the Adverse Eventsfor the 6 cohorts is shown in Table 6 below:

TABLE 6 Summary of Safety - Adverse Event Overview Q2W Q3W 0.1 mg/kg 0.3mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 15 mg/kg N = 4 N = 4 N = 3 N = 3 N = 245N = 6 Any AE 4 (100%)  4 (100%)  3 (100%)  3 (100%)  178 (72.7%)  6(100%)  G3/4 AE 1 (25.0%) 0 1 (33.3%) 1 (33.3%) 60 (24.5%) 2 (33.3%) SAE1 (25.0%) 2 (50.0%) 1 (33.3%) 1 (33.3%) 49 (20.0%) 2 (33.3%) AE to D/C 11 (25 0%) 0 0 15 (6.1%)  0 Related AE 2 (50.0%) 1 (25.0%) 1 (33.3%) 1(33.3%) 82 (33.5%) 5 (83.3%) Related G3/4 AE 0 0 0 0 12 (4.9%)  1(16.7%) Related AE to D/C* 0 0 0 0 1 (0.4%) 0

An extremely low incidence of ADAs was observed over the dose range of0.1 to 3 mg/kg. In particular, only 1 of 15 patients who received a doseof dose range of 0.1 to 1 mg/kg tested ADA positive with PK/PDimplications. There was no evidence for impact on drug exposure ortarget suppression over the dose range of 0.1 to 1.0 mg/kg.

(e) Discussion

This study demonstrates that MEDI4736 has favorable pK properties and isgenerally well tolerated. In addition, MEDI4736 is effective in treatingsolid tumors (including, but not limited to melanoma, non-small celllung cancer, pancreatic adenocarcinoma, uveal melanoma, squamous cellcarcinoma of the head and neck, gastroesophageal cancer, andhepatocellular carcinoma) while producing a low incidence of ADA.Clinical benefit was observed at all dose levels tested, with activityreported as early as 6 weeks.

Example 3: Quantitation of Soluble B7-H1

Soluble B7-H1 (not bound to MED4736) was measured using anelectrochemiluminescent (ECL) based assay. The specific procedure usedto assay soluble B7-H1 in human serum is shown below.

(a) Plate Preparation

I-Block Buffer (IBB) (MedImmune) was equilibrated to room temperature(RT) and transferred to a reagent reservoir (Fisher Scientific#07-200-127). 150 μl of IBB was pipetted into each plate well ofstreptavidin-coated plates (Meso Scale Discovery (“MSD”) Cat.L11SA/L15SA). The plates were covered and incubated at RT for a minimumof one hour (no more than four hours) with shaking at approximately 450rpm on an orbital plate shaker.

Capture Antibody Working Solution (WS) was prepared immediately beforeuse using IBB at RT. The capture antibody is a biotinylated anti-humanB7-H1 IgG1 TM antibody, clone 2.7A4 as described in US 2013/0034559.First, at least 100 μL of capture antibody stock solution waspre-diluted in IBB to a concentration of 1000 μg/ml as shown in Table 7below. Then, 250 μg/mL Capture Antibody WS was prepared in IBB inpolypropylene tubes using the volumes indicated in Table 8 below.Capture Antibody WS was then transferred to a reagent reservoir.

TABLE 7 Pre-dilution of Capture Antibody Stock Solution assuming stockconcentration of 10 mg/mL Source Solution Target IBB Vol Source VolDilution Solution Concentration (μL) Solution (μL) Factor Capture 1000μg/mL 90 Capture 10 10 Antibody Antibody Pre-Dilution Stock (PD)Solution

TABLE 8 Preparation of Capture Antibody WS from Capture Antibody PDSource Solution Target IBB Vol Source Vol Dilution SolutionConcentration (μL) Solution (μL) Factor Pre-Dilution 10 μg/mL  990Capture  10 100 A Antibody PD Capture 250 ng/mL 7800 Pre-Dilution 200 40 Antibody A WS

Plate blocking was ended by washing plates with 3×300 μL 1×ELISA WashBuffer (1×PBS, 0.05% Tween 20) using plate washer. Plates were blotteddry and immediately coated with 35 μL per well of Capture Antibody WS.Plates were sealed and incubated for 1 hour at RT while shaking atapproximately 450 rpm on an orbital plate shaker.

(b) Test Sample, Reference Sample, and Quality Control SamplePreparation

Human serum samples to be tested were thawed at RT and gently mixeduntil uniform. These samples were used undiluted.

Reference Standard Stock Solutions (RS Stock) of recombinant B7-H1 werepre-diluted in Assay Matrix (AM): Neal Calf Serum (Lonza, Cat 14-401F)to a concentration of 47 μg/mL as indicated in Table 9 below. RSPre-Dilution was serially diluted in AM as indicated in Table 10 belowfor final reference standard concentrations of 2000 (S1), 1000 (S2), 500(S3), 250 (S4), 125 (S5), 62.5 (S6), 31.3 (S7), 15.6 (S8), 7.8 (S9), and3.9 (S10) pg/mL. An AM-alone sample was also included. Dilutions wereprepared in polypropylene titer tubes or equivalent.

TABLE 9 Pre-dilution of Reference Standard Stock Solution assuming RSStock Concentration of 470 μg/mL. Assay Source Matrix Solution TargetVol Source Vol Dilution Solution Concentration (μL) Solution (μL) FactorRS Pre- 47 μg/mL 90 RS Stock, 10 10 Dilution 470 μg/mL

TABLE 10 Preparation of Reference Standard Dilutions Assay Source MatrixSolution Target Vol Source Vol Dilution Solution Concentration (μL)Solution (μL) Factor Pre-Dilution 4700 μg/mL  90 RS Pre-Dil. 10 10.0 A47 μg/mL Pre-Dilution 47 ng/mL 990 Pre-Dilution 10 100.0 B A S1  2000pg/ml 800 Pre-Dilution 35.6 23.5 B S2  1000 pg/ml 400 S1 400 2.0 S3  500pg/ml 400 S2 400 2.0 S4  250 pg/ml 400 S3 400 2.0 S5  125 pg/ml 400 S4400 2.0 S6  62.5 pg/ml 400 S5 400 2.0 S7  31.3 pg/mL 400 S6 400 2.0 S8 15.6 pg/mL 400 S7 400 2.0 S9  7.8 pg/mL 400 S8 400 2.0 S10 3.9 pg/mL 400S9 400 2.0 AM 0 pg/mL 400 N/A N/A N/A

Quality Control (QC) sample Pre-Dilutions in AM as well as High, Medium,and Low QC samples were prepared in polypropylene tubes or equivalent asindicated in Table 11 below. The QC stock solution used was recombinantB7-H1 protein in 90% calf serum (Lonza, Cat. 14-401F).

TABLE 11 Preparation of QC Sample Dilutions Assay Source Matrix SolutionTarget Vol Source Vol Dilution Solution Concentration (μL) Solution (μL)Factor Pre-Dilution 4700 μg/mL  90 QCS, 10 10.0 A 47 μg/mL Pre-Dilution47 ng/mL 990 Pre-Dilution 10 100.0 B A Pre-Dilution 4.7 pg/ml 180Pre-Dilution 20 10.0 C B Pre-Dilution 0.47 pg/ml 180 Pre-Dilution 2010.0 D C QC1 (High) 800 pg/ml 400 Pre-Dilution 6.9 58.8 B QC2 (Med) 200pg/ml 400 Pre-Dilution 17.8 23.5 C QC3 (Low) 32 pg/ml 400 Pre-Dilution29.2 14.7 D(c) Soluble B7-H1 Detection

Prepared plates were washed with 3×300 μL 1×ELISA Wash Buffer andblotted dry. Test Samples, Reference Standards, Quality Controls, andAssay Matrix alone were transferred into duplicate wells on plates (35μl each). Plates were sealed and incubated for 30 minutes at RT withshaking at approximately 450 rpm on an orbital plate shaker.

Primary Detection Antibody Working Solution (WS) was prepared in IBB (1μg/mL) in polypropylene tubes as indicated in Table 12 below. Theprimary detection antibody was mouse anti-human B7-H1 IgG1 antibodyclone 130021 (R&D Systems, Cat. MAB1561) (0.5 mg/ml).

TABLE 12 Preparation of Primary Detection Antibody Working Solution (WS)Source Solution Target IBB Vol Source Vol Dilution SolutionConcentration (μL) Solution (μL) Factor Primary 1 μg/mL 8000 Primary 16500 Detection Detection Antibody Antibody WS Stock Solution, 500 μg/mL

Plates were removed from the shaker and washed 3×300 μL 1×ELISA WashBuffer and blotted dry. Primary Detection Antibody WS was transferredinto a reagent reservoir, and then 35 μl was pipetted into each platewell. The plates were sealed again and incubated at RT for an hour withshaking at approximately 450 rpm on an orbital plate shaker.

Secondary Detection Antibody Working Solution (WS) was prepared in IBB(1 μg/mL) in polypropylene tubes as indicated in Table 13 below. Thesecondary detection antibody was ruthenium-labeled goat anti-mouse B7-H1polyclonal antibody (MSD, Cat. R32AC-1) (0.5 mg/ml). Secondary DetectionAntibody WS was protected from light.

TABLE 13 Preparation of Secondary Detection Antibody Working Solution(WS) Source Solution Target IBB Vol Source Vol Dilution SolutionConcentration (μL) Solution (μL) Factor Secondary 1 μg/mL 8000 Secondary16 500 Detection Detection Antibody Antibody WS Stock Solution, 500μg/mL

Plates were removed from shaker and washed 3×300 μL 1×ELISA Wash Bufferand blotted dry. Secondary Detection Antibody WS was transferred into areagent reservoir, and then 35 μl was pipetted into each plate well. Theplates were sealed again and incubated at RT for an hour with shaking atapproximately 450 rpm on an orbital plate shaker while protected fromlight.

Read Buffer T (1×) was prepared by diluting Read Buffer T (4×) (MSD Cat.R92TC-1) reagent in Cell Culture-Grade Water in polypropylene tubes asindicated in Table 14 below.

TABLE 14 Preparation of Secondary Detection Antibody Working Solution(WS) Cell Culture- Source Grate Solution Target Water Vol Source VolDilution Solution Concentration (μL) Solution (μL) Factor 1× Read 1× 154× Read 5 4 Buffer T Buffer T

Plates were removed from shaker and washed 3×300 μL 1×ELISA Wash Buffer.Plates were covered and blotted dry only immediately before addition of1× Read Buffer T. Read Buffer T (1×) was transferred into a reagentreservoir. Assay plates were uncovered to be read and blotted dry. ReadBuffer T (1×) was pipetted into all wells of the assay plate (150 μl),and the plate was read within 5 minutes.

(d) Data Analysis

Data was transferred into SoftMax® Pro GxP v. 5.2 software (MolecularDevices) for analysis, and the Reference Standard concentrations wereplotted against the ECL signal values using a 1/y² weighted 4-parameterlogistical curve fitting model.

The pg/ml of sB7-H1 for all Reference Standards and QC sample dilutionswere (back-)calculated. The coefficient of variation (% CV) of duplicatewells for each Reference Standard and QC sample dilution was alsocalculated. These data were used to determine if a plate met theAcceptance Criteria. A plate was considered valid if the followingAcceptance Criteria were met:

1—the mean % recovery for Reference Standards levels S2 to S7 was within±25% and level S8 was within ±30% of the nominal concentration;

2—the % CV for each back-calculated concentration of Reference Standardlevels S2 to S7 was ≤25%, and level S8≤30%;

3—the mean % recovery for each QC level was within ±25% of the nominalconcentration; and

4—the % CV for the back-calculated concentration for at least 2 out of 3QC levels was ≤25%.

For valid plates, the pg/ml of sB7-H1 in each sample was calculatedusing the Reference Standard. Since Test Samples were tested neat, thedilution factor for each Test Sample is 1.0, and no dilution factorcorrection was needed. The resulting data represents sB7-H1concentrations in 100% serum.

The data for the Test Samples was also reviewed to determine if it metthe Acceptance Criteria. Test Sample readings were considered valid ifthe following Acceptance Criteria were met:

1—the back-calculated concentration of both replicates fell within theassay working range;

2—the % CV for the mean back-calculated concentration of the Test Samplewas ≤25%.

In the event that the back-calculated concentration for one of the Testsamples fell within the assay working range and the other below theassay lower limit of quantitation (LLOQ) or above the assay upper limitof quantitation ULOQ the following criteria were applied:

-   -   If the % CV of the mean back-calculated concentration is >25%,        the test sample was considered invalid.    -   If the % CV of the mean back-calculated concentration was ≤25%        and the mean back-calculated concentration was within the assay        working range, the Test Sample was considered valid and the mean        back-calculated concentration of the Test Sample was reported.    -   If the % CV of the mean back-calculated concentration was ≤25%,        the Test Sample was considered valid and was reported as below        the limit of quantitation or above the limit of quantitation.

In the event that the back-calculated concentration for both Test Samplereplicates fell below the assay LLOQ, the Test Sample was consideredvalid and reported as below the limit of quantitation.

In the event that the back-calculated concentration for one of the TestSample replicates fell below the assay working range and the otherreplicate was out of range, the following criteria were applied:

-   -   If the ECL value of the out of range replicate was below the        mean LLOQ ECL of the assay, the Test Sample was considered valid        and reported as below the limit of quantitation.    -   If the ECL value of the out of range replicate was above the        mean ULOQ ECL of the assay, the Test Sample was considered        invalid.

In the event that the back-calculated concentration for both Test Samplereplicates fell above the assay ULOQ, the Test Sample was consideredvalid and reported as above the limit of quantitation.

In the event that the back-calculated concentration for one of the TestSample replicates fell above the assay working range and the otherreplicate was out of range the following criteria were applied:

-   -   If the ECL value of the out of range replicate was above the        mean ULOQ ECL of the assay, the Test Sample was considered valid        and reported as above the limit of quantitation.    -   If the ECL value of the out of range replicate was below the        mean LLOQ ECL of the assay, the Test Sample was considered        invalid.

In the event that the back-calculated concentration for one of the TestSample replicates fell within the assay working range and the otherreplicate was out of range, the Test Sample was considered invalid.

In the event that the back-calculated concentration for both Test Samplereplicates was out of range the following criteria were applied.

-   -   If both ECL values fell below the mean LLOQ ECL of the assay,        Test Sample was considered valid and reported as below the limit        of quantitation.    -   If both ECL values fell above the mean ULOQ ECL of the assay,        the Test Sample was considered valid and reported as above the        limit of quantitation.    -   If the ECL value of one replicate was below the mean LLOQ ECL of        the assay and the ECL value of the other replicate was above the        ULOQ ECL, the Test Sample was considered invalid.

These procedures were used to determine the soluble B7-H1 in human serumsamples as provided above in Examples 1 and 2 above.

Example 4: PD-L1 Expression Drives Patient Response Rate

Subject tissue of NSCLC patients was characterized for PDL1 expressionby immunohistochemistry in formalin fixed and paraffin embedded tissuesamples. A sample was determined to be “PD-L1 positive” if the samplecontained 25% or more tumor cells with PDL1 membrane staining. Theprevalence of such samples in the NSCLC population using the PDL1 assaywas 20-40%.

A cutoff and scoring algorithm has been determined by evaluating samplesfrom ˜60 patients in the Phase I trial (CP1108). With the cutoffestablished for Phase 3 trials, approximately 40% of NSCLC patients arePD-L1 positive (Table 15, below).

TABLE 15 PD-L1 Expression is a Key Driver of Response PDL1+ Population-Agent PDL1+ PDL1− NSCLC MEDI4736 39%* (5/13) 5%* (1/19) 39% (24/62)*Patients treated <12 wks prior to the data cut censored

Patients identified as having PDL1-expressing tumors are more likely torespond to MEDI4736 treatment than unselected patients (Table 16,below). There was an objective response rate of fifty percent inPDL1-positive NSCLC patients treated with 10 mg/kg MEDI4736 for greaterthan 16-24 weeks (Table 16). This dramatic response rate was notobserved in PDL1 negative or unselected patients (Table 16). Theseresults indicate that PDL1 expression is a key driver of response inNSCLC.

TABLE 16 Objective Response Evolves Over Time Time Since Enrollment(MEDI4736 10 mg/kg) ≥24 wks ≥16 wks ≥12 wks ≥6 wks PD-L1⁺ 50% (1/2)  50%(2/4)  39% (5/13) 25% (5/20) PD-L1⁻ 17% (1/6)  11% (1/9)   5% (1/19)  6%(2/35) Unselected* 10% (2/20) 11% (3/27) 13% (6/47)  9% (7/75)

Complete or partial responses (CR/PR) to MEDI4736 were observed in fiftypercent of PDL1-positive NSCLC patients treated with 10 mg/kg MEDI4736for greater than 16-24 weeks (Table 17, below). Early responses toMEDI4736 treatment can be observed in just 6-12 weeks (Table 17).

TABLE 17 Response Rate in PDL1⁺ NSCLC Patients (MEDI4736, 10 mg/kg) TimeSince ≥24 wks ≥16 wks ≥12 wks ≥6 wks Enrollment (dosed ≤ Nov. 4, 2013)(dosed ≤ Dec. 30, 2013) (dosed ≤ Jan. 27, 2014) (dosed ≤ Mar. 10, 2014)PD-L1⁺, n 2 4 13 20 CR/PR, % (n) 50% (1) 50% (2) 38.5% (5) 25% (5) A keydriver of response to MEDI4736 is PD-L1⁺ status

Unselected patients did not show the same high rate of responsiveness toMEDI4736 (Table 18, below).

TABLE 18 Response Rate in Unselected NSCLC Patients (MEDI4736, AllDoses) Time Since ≥24 wks ≥16 wks ≥12 wks ≥6 wks Enrollment (dosed ≤Nov. 4, 2013) (dosed ≤ Dec. 30, 2013) (dosed ≤ Jan. 27, 2014) (dosed ≤Mar. 10, 2014) Response 31 38 58 87 Evaluable, n CR/PR, % (n) 16.1% (5)15.8% (6) 15.5% (9) 11.5% (10)

A summary of Disease Response is provided at Table 19.1 (10 mg/kg Q2W).Where the tumor samples met the criteria for being PDL1-positive, i.e.,contained 25% or more tumor cells with PDL1 membrane staining(MSCORE >25%), a 40% response rate was observed in patients treated forat least 16 to 24 weeks or more. A thirty-three percent complete orpartial response rate was observed in subjects with squamous cellcarcinoma of the head and neck (SCCHN) treated with 10 mg/kg Q2W for atleast 16 to 24 weeks or more.

A summary of disease response at all Dose Levels is shown at Table 19.2.Complete or partial response rates were highest in patients that met thecriteria for PDL1-positive NSCLC (Table 19.2). A greater benefit wasseen in NSCLC and SCCHN at longer treatment times (Table 19.2). Table19.3 shows a summary of disease response in subjects with doseescalation (Q2W and Q3W).

TABLE 19.1 Summary of Disease Response - 10 mg/kg Q2W SUBJECTS WITHPOTENTIAL FOLLOW-UP OF =24 Weeks =16 Weeks Dosed <= Nov. 4, 2013 Dosed<= Dec. 30, 2013 ALL EVALUABLE[4] ALL EVALUABLE[4] ALL SUBJECTS N 55 53118 112 CR/PR[1] 4 (7.3%)  4 (7.5%)  10 (8.5%)  10 (8.9%)  MINORRESPONSE[2] 7 (12.7%) 7 (13.2%) 15 (12.7%)  15 (13.4%)  UNCONVENTIONAL 3(5.5%)  3 (5.7%)  3 (2.5%)  3 (2.7%)  RESPONSE[3] NSCLC N 21 20 29 27CR/PR[1] 2 (9.5%)  2 (10.0%) 3 (10.3%) 3 (11.1%) MINOR RESPONSE[2] 2(9.5%)  2 (10.0%) 2 (6.9%)  2 (7.4%)  PD-L1 STATUS AVAILABLE N 8 8 14 13( ) PD-L1 POSITIVE N 2 2 4 4 (MSCORE >=25%) CR/PR[1] 1 (50.0%) 1 (50.0%)2 (50.0%) 2 (50.0%) MINOR RESPONSE[2] 1 (50.0%) 1 (50.0%) 1 (25.0%) 1(25.0%) PD-L1 STATUS AVAILABLE N 19 18 27 25 PD-L1 POSITIVE N 7 7 10 10(>=25% OR MEDI CR/PR[1] 1 (14.3%) 1 (14.3%) 2 (20.0%) 2 (20.0%) >=5%)MINOR RESPONSE[2] 2 (28.6%) 2 (28.6%) 2 (20.0%) 2 (20.0%) PD-L1 STATUS(FRESH) N 18 17 25 23 PD-L1 POSITIVE (FRESH) N 5 5 7 7 (>=25% OR MEDICR/PR[1] 1 (20.0%) 1 (20.0%) 1 (14.3%) 1 (14.3%) >=5%) MINOR RESPONSE[2]2 (40.0%) 2 (40.0%) 2 (28.6%) 2 (28.6%) PD-L1 NEGATIVE N 6 6 10 9 (<25%)CR/PR[1] 1 (16.7%) 1 (16.7%) 1 (10.0%) 1 (11.1%) MINOR RESPONSE[2] 0(0.0%)  0 (0.0%)  0 (0.0%)  0 (0.0%)  SCCHN N 3 3 15 15 CR/PR[1] 1(33.3%) 1 (33.3%) 3 (20.0%) 3 (20.0%) MINOR RESPONSE[2] 0 (0.0%)  0(0.0%)  2 (13.3%) 2 (13.3%) UNCONVENTIONAL 1 (33.3%) 1 (33.3%) 1 (6.7%) 1 (6.7%)  RESPONSE[3] SUBJECTS WITH POTENTIAL FOLLOW-UP OF =12 Weeks =6Weeks Dosed <= Jan. 27, 2014 Dosed <= Mar. 10, 2014 ALL EVALUABLE[4] ALLEVALUABLE[4] ALL SUBJECTS N 166 159 264 246 CR/PR[1] 14 (8.4%)  14(8.8%)  18 (6.8%)  18 (7.3%)  MINOR RESPONSE[2] 21 (12.7%)  21 (13.2%) 38 (14.4%)  38 (15.4%)  UNCONVENTIONAL 3 (1.8%)  3 (1.9%)  3 (1.1%)  3(1.2%)  RESPONSE[3] NSCLC N 50 47 84 75 CR/PR[1] 6 (12.0%) 6 (12.8%) 7(8.3%)  7 (9.3%)  MINOR RESPONSE[2] 3 (6.0%)  3 (6.4%)  9 (10.7%) 9(12.0%) PD-L1 STATUS AVAILABLE N 34 32 62 55 ( ) PD-L1 POSITIVE N 14 1324 20 (MSCORE >=25%) CR/PR[1] 5 (35.7%) 5 (38.5%) 5 (20.8%) 5 (25.0%)MINOR RESPONSE[2] 1 (7.1%)  1 (7.7%)  2 (8.3%)  2 (10.0%) PD-L1 STATUSAVAILABLE N 47 44 76 68 PD-L1 POSITIVE N 20 19 32 28 (>=25% OR MEDICR/PR[1] 5 (25.0%) 5 (26.3%) 5 (15.6%) 5 (17.9%) >=5%) MINOR RESPONSE[2]2 (10.0%) 2 (10.5%) 3 (9.4%)  3 (10.7%) PD-L1 STATUS (FRESH) N 45 42 7365 PD-L1 POSITIVE (FRESH) N 15 14 25 21 (>=25% OR MEDI CR/PR[1] 4(26.7%) 4 (28.6%) 4 (16.0%) 4 (19.0%) >=5%) MINOR RESPONSE[2] 2 (13.3%)2 (14.3%) 2 (8.0%)  2 (9.5%)  PD-L1 NEGATIVE N 20 19 38 35 (<25%)CR/PR[1] 1 (5.0%)  1 (5.3%)  2 (5.3%)  2 (5.7%)  MINOR RESPONSE[2] 1(5.0%)  1 (5.3%)  5 (13.2%) 5 (14.3%) SCCHN N 22 22 44 41 CR/PR[1] 3(13.6%) 3 (13.6%) 4 (9.1%)  4 (9.8%)  MINOR RESPONSE[2] 2 (9.1%)  2(9.1%)  5 (11.4%) 5 (12.2%) UNCONVENTIONAL 1 (4.5%)  1 (4.5%)  1 (2.3%) 1 (2.4%)  RESPONSE[3] [1]CR/PR: All confirmed and unconfirmed (based oneither RECIST for 10 mg/kg or iRRC for other dose-levels) [2]MinorResponse: max reduction in TLs >0-<30% and no PD due to new lesion orNTLs [3]Unconventional Response: max reduction in TLs >30% & PD due tonew lesion [4]Evaluable population: all patients with disease assessmentor died/discontinued due to clinical PD without any disease assessmentREFER TO SUPPORTING DATA LISTING(S) 16.3.2./SASDATA/cars/dev/medi4736/cd1108/asco02/tables/disresp_mur4.sas DRAFT18MAY2014 16:54:02

TABLE 19.2 Summary of Disease Response - All Dose Levels SUBJECTS WITHPOTENTIAL FOLLOW-UP OF ≥24 Weeks ≥16 Weeks Dosed <= Nov. 4, 2013 Dosed<= Dec, 30, 2013 ALL EVALUABLE[4] ALL EVALUABLE[4] ALL SUBJECTS N 74 72138 132 CR/PR[1] 9 (12.2%) 9 (12.5%) 15 (10.9%)  15 (11.4%)  MINORRESPONSE[2] 11 (14.9%)  11 (15.3%)  19 (13.8%)  19 (14.4%) UNCONVENTIONAL 3 (4.1%)  3 (4.2%)  3 (2.2%)  3 (2.3%)  RESPONSE[3] NSCLCN 32 31 40 38 CR/PR[1] 5 (15.6%) 5 (16.1%) 6 (15.0%) 6 (15.8%) MINORRESPONSE[2] 5 (15.6%) 5 (16.1%) 5 (12.5%) 5 (13.2%) PD-L1 STATUSAVAILABLE N 8 8 14 13 PD-L1 POSITIVE N 2 2 4 4 (MSCORE >=25%) CR/PR[1] 1(50.0%) 1 (50.0%) 2 (50.0%) 2 (50.0%) MINOR RESPONSE[2] 1 (50.0%) 1(50.0%) 1 (25.0%) 1 (25.0%) PD-L1 STATUS AVAILABLE N 24 23 32 30 PD-L1POSITIVE N 8 8 11 11 (>=25% OR MEDI CR/PR[1] 1 (12.5%) 1 (12.5%) 2(18.2%) 2 (18.2%) >=5%) MINOR RESPONSE[2] 2 (25.0%) 2 (25.0%) 2 (18.2%)2 (18.2%) PD-L1 STATUS (FRESH) N 18 17 25 23 PD-L1 POSITIVE (FRESH) N 55 7 7 (>=25% OR MEDI CR/PR[1] 1 (20.0%) 1 (20.0%) 1 (14.3%) 1(14.3%) >=5%) MINOR RESPONSE[2] 2 (40.0%) 2 (40.0%) 2 (28.6%) 2 (28.6%)PD-L1 NEGATIVE N 6 6 10 9 (<25%) CR/PR[1] 1 (16.7%) 1 (16.7%) 1 (10.0%)1 (11.1%) MINOR RESPONSE[2] 0 (0.0%)  0 (0.0%)  0 (0.0%)  0 (0.0%) SCCHN N 3 3 15 15 CR/PR[1] 1 (33.3%) 1 (33.3%) 3 (20.0%) 3 (20.0%) MINORRESPONSE[2] 0 (0.0%)  0 (0.0%)  2 (13.3%) 2 (13.3%) UNCONVENTIONAL 1(33.3%) 1 (33.3%) 1 (6.7%)  1 (6.7%)  RESPONSE[3] SUBJECTS WITHPOTENTIAL FOLLOW-UP OF ≥12 Weeks ≥6 Weeks Dosed <= Jan. 27, 2014 Dosed<= Mar. 10, 2014 ALL EVALUABLE[4] ALL EVALUABLE[4] ALL SUBJECTS N 186179 285 267 CR/PR[1] 19 (10.2%)  19 (10.6%)  23 (8.1%)  23 (8.6%)  MINORRESPONSE[2] 25 (13.4%)  25 (14.0%)  43 (15.1%)  43 (16.1%) UNCONVENTIONAL 3 (1.6%)  3 (1.7%)  3 (1.1%)  3 (1.1%)  RESPONSE[3] NSCLCN 61 58 96 87 CR/PR[1] 9 (14.8%) 9 (15.5%) 10 (10.4%)  10 (11.5%)  MINORRESPONSE[2] 6 (9.8%)  6 (10.3%) 13 (13.5%)  13 (14.9%)  PD-L1 STATUSAVAILABLE N 34 32 62 55 PD-L1 POSITIVE N 14 13 24 20 (MSCORE >=25%)CR/PR[1] 5 (35.7%) 5 (38.5%) 5 (20.8%) 5 (25.0%) MINOR RESPONSE[2] 1(7.1%)  1 (7.7%)  2 (8.3%)  2 (10.0%) PD-L1 STATUS AVAILABLE N 52 49 8274 PD-L1 POSITIVE N 21 20 33 29 (>=25% OR MEDI CR/PR[1] 5 (23.8%) 5(25.0%) 5 (15.2%) 5 (17.2%) >=5%) MINOR RESPONSE[2] 2 (9.5%)  2 (10.0%)3 (9.1%)  3 (10.3%) PD-L1 STATUS (FRESH) N 45 42 73 65 PD-L1 POSITIVE(FRESH) N 15 14 25 21 (>=25% OR MEDI CR/PR[1] 4 (26.7%) 4 (28.6%) 4(16.0%) 4 (19.0%) >=5%) MINOR RESPONSE[2] 2 (13.3%) 2 (14.3%) 2 (8.0%) 2 (9.5%)  PD-L1 NEGATIVE N 20 19 38 35 (<25%) CR/PR[1] 1 (5.0%)  1(5.3%)  2 (5.3%)  2 (5.7%)  MINOR RESPONSE[2] 1 (5.0%)  1 (5.3%)  5(13.2%) 5 (14.3%) SCCHN N 22 22 44 41 CR/PR[1] 3 (13.6%) 3 (13.6%) 4(9.1%)  4 (9.8%)  MINOR RESPONSE[2] 2 (9.1%)  2 (9.1%)  5 (11.4%) 5(12.2%) UNCONVENTIONAL 1 (4.5%)  1 (4.5%)  1 (2.3%)  1 (2.4%) RESPONSE[3] [1]CR/PR: All confirmed and unconfirmed (based on eitherRECIST for 10 mg/kg or iRRC for other dose-levels) [2]Minor Response:max reduction in TLs >0-<30% and no PD due to new lesion or NTLs[3]Unconventional Response: max reduction in TLs >30% & PD due to newlesion [4]Evaluable population: all patients with disease assessment ordied/discontinued due to clinical PD without any disease assessmentREFER TO SUPPORTING DATA LISTING(S) 16.3.2./SASDATA/cars/dev/medi4736/cd1108/asco02/tables/disresp_mur4.sas DRAFT18MAY2014 16:54:04

TABLE 19.3 Summary of Disease Response—Dose Escalation SubjectsIncluding Q2W and Q3W SUBJECTS WITH POTENTIAL FOLLOW-UP OF ≥24 Weeks ≥16Weeks Dosed <= Nov. 4, 2013 Dosed <= Dec. 30, 2013 ALL EVALUABLE[4] ALLEVALUABLE[4] ALL SUBJECTS N 25 25 26 26 CR/PR[1] 5 (20.0%) 5 (20.0%) 5(19.2%) 5 (19.2%) MINOR RESPONSE[2] 4 (16.0%) 4 (16.0%) 4 (15.4%) 4(15.4%) NSCLC N 13 13 13 13 CR/PR[1] 3 (23.1%) 3 (23.1%) 3 (23.1%) 3(23.1%) MINOR RESPONSE[2] 3 (23.1%) 3 (23.1%) 3 (23.1%) 3 (23.1%) PD-L1STATUS AVAILABLE N 6 6 6 6 PD-L1 POSITIVE N 2 2 2 2 (>=25% OR MEDI >=5%)SUBJECTS WITH POTENTIAL FOLLOW-UP OF ≥12 Weeks ≥6 Weeks Dosed <= Jan.27, 2014 Dosed <= Mar. 10, 2014 ALL EVALUABLE[4] ALL EVALUABLE[4] ALLSUBJECTS N 26 26 27 27 CR/PR[1] 5 (19.2%) 5 (19.2%) 5 (18.5%) 5 (18.5%)MINOR RESPONSE[2] 4 (15.4%) 4 (15.4%) 5 (18.5%) 5 (18.5%) NSCLC N 13 1314 14 CR/PR[1] 3 (23.1%) 3 (23.1%) 3 (21.4%) 3 (21.4%) MINOR RESPONSE[2]3 (23.1%) 3 (23.1%) 4 (28.6%) 4 (28.6%) PD-L1 STATUS AVAILABLE N 6 6 7 7PD-L1 POSITIVE N 2 2 2 2 (>=25% OR MEDI >=5%) [1]CR/PR: All confirmedand unconfirmed (based on either RECIST for 10 mg/kg or iRRC for otherdose-levels) [2]Minor Response: max reduction in TLs >0-<30% and no PDdue to new lesion or NTLs [3]Unconventional Response: max reduction inTLs >30% & PD due to new lesion [4]Evaluable population: all patientswith disease assessment or died/discontinued due to clinical PD withoutany disease assessment REFER TO SUPPORTING DATA LISTING(S) 16.3.2./SASDATA/cars/dev/medi4736/cd1108/asco02/tables/disresp_mur4.sas DRAFT18MAY2014 16:54:06

Further patient response rates are shown in FIGS. 25A-C. The response ofNon-squamous NSCLC patients and Squamous NSCLC patients to MEDI4736treatment is shown in FIG. 25A. The response rate relative to tumorPD-L1 status (positive, negative, or NA) is shown in FIGS. 25B and C.The data demonstrate an increased response rate in patients with PD-L1positive tumors.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificaspects of the disclosure described herein. Such equivalents areintended to be encompassed by the following claims.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationscan be practiced within the scope of the appended claims.

SEQUENCE LISTING

SEQ ID NO: 1 > PCT/US2010/058007_77 Sequence 77 fromPCT/US2010/058007 Organism: Homo sapiensEIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFG QGTKVEIKSEQ ID NO: 2 > PCT/US2010/058007_72 Sequence 72 fromPCT/US2010/058007 Organism: Homo sapiensEVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREG GWFGELAFDYWGQGTLVTVSSVH CDR1 SEQ ID NO: 3 > PCT/US2010/058007_73 Sequence 73 fromPCT/US2010/058007 Organism: Homo sapiens GFTFSRYWMS VH CDR2SEQ ID NO: 4 > PCT/US2010/058007_74 Sequence 74 fromPCT/US2010/058007 Organism: Homo sapiens NIKQDGSEKYYVDSVKG VH CDR3SEQ ID NO: 5 > PCT/US2010/058007_75 Sequence 75 fromPCT/US2010/058007 Organism: Homo sapiens EGGWFGELAFDY VL CDR1SEQ ID NO: 6 > PCT/US2010/058007_78 Sequence 78 fromPCT/US2010/058007 Organism: Homo sapiens RASQRVSSSYLA VL CDR2SEQ ID NO: 7 > PCT/US2010/058007_79 Sequence 79 fromPCT/US2010/058007 Organism: Homo sapiens DASSRAT VL CDR3 SEQ ID NO: 8 >PCT/US2010/058007_80 Sequence 80 fromPCT/US2010/058007 Organism: Homo sapiens QQYGSLPWT

What is claimed is:
 1. A method of treating a patient identified ashaving non-small cell lung carcinoma (NSCLC), the method comprisingadministering to the patient 10 mg/kg of an isolated antibody or anantigen-binding fragment thereof that specifically binds to PD-L1, theisolated antibody or fragment thereof comprising: a VH CDR1 having theamino acid sequence of SEQ ID NO: 3; a VH CDR2 having the amino acidsequence of SEQ ID NO: 4; a VH CDR3 having the amino acid sequence ofSEQ ID NO: 5; a VL CDR1 having the amino acid sequence of SEQ ID NO: 6;a VL CDR2 having the amino acid sequence of SEQ ID NO: 7; and a VL CDR3having the amino acid sequence of SEQ ID NO: 8, wherein at least 25% ofthe NSCLC tumor cells are PD-L1 positive.
 2. The method of claim 1,wherein the administration is repeated every 14 to 21 days.
 3. Themethod of claim 2, wherein the administration is repeated every 14 days.4. The method of claim 1, wherein the tumor is refractory to at leastone chemotherapeutic agent.
 5. The method of claim 4, wherein thechemotherapeutic agent is Vemurafenib, Afatinib, Cetuximab, Carboplatin,Bevacizumab, Erlotinib, or Pemetrexed.
 6. The method of claim 1, whereinthe tumor is a non-small cell lung cancer that is a squamous cellcarcinoma.
 7. The method of claim 1, wherein the tumor is a non-smallcell lung cancer that is a non-squamous cell carcinoma.
 8. The method ofclaim 1, wherein PD-L1 status is detected using immunohistochemistry. 9.A method of treating a patient identified as having non-small cell lungcarcinoma (NSCLC), the method comprising administering to the patient 15mg/kg of an isolated antibody or an antigen-binding fragment thereofthat specifically binds to PD-L1, the isolated antibody or fragmentthereof comprising: a VH CDR1 having the amino acid sequence of SEQ IDNO: 3; a VH CDR2 having the amino acid sequence of SEQ ID NO: 4; a VHCDR3 having the amino acid sequence of SEQ ID NO: 5; a VL CDR1 havingthe amino acid sequence of SEQ ID NO: 6; a VL CDR2 having the amino acidsequence of SEQ ID NO: 7; and a VL CDR3 having the amino acid sequenceof SEQ ID NO: 8, wherein at least 25% of the NSCLC tumor cells are PD-L1positive.
 10. A method of treating a patient identified as havingnon-small cell lung carcinoma (NSCLC), the method comprisingadministering to the patient 10 mg/kg of an isolated antibody or anantigen-binding fragment thereof that specifically binds to PD-L1, theisolated antibody or fragment thereof comprising a VL having the aminoacid sequence of SEQ ID NO: 1; and a VH having the amino acid sequenceof SEQ ID NO: 2, wherein at least 25% of the NSCLC tumor cells are PD-L1positive.
 11. The method of claim 10, wherein the administration isrepeated every 14 to 21 days.
 12. The method of claim 11, wherein theadministration is repeated every 14 days.
 13. The method of claim 10,wherein the tumor is refractory to at least one chemotherapeutic agent.14. The method of claim 13, wherein the chemotherapeutic agent isVemurafenib, Afatinib, Cetuximab, Carboplatin, Bevacizumab, Erlotinib,or Pemetrexed.
 15. The method of claim 10, wherein the tumor is anon-small cell lung cancer that is a squamous cell carcinoma.
 16. Themethod of claim 10, wherein the tumor is a non-small cell lung cancerthat is a non-squamous cell carcinoma.
 17. The method of claim 10,wherein PD-L1 status is detected using immunohistochemistry.
 18. Themethod of claim 9, wherein the isolated antibody or fragment thereofcomprises a VL having the amino acid sequence of SEQ ID NO: 1; and a VHhaving the amino acid sequence of SEQ ID NO: 2.